Rash is the most common side effect of epidermal growth factor receptor (EGFR) inhibitors, occurring in >70% of cancer patients who take these drugs. This rash occurs on the face, trunk, and extremities and, when severe, can lead to discontinuation of cancer therapy. EGFR inhibitors are being prescribed with increasing frequency and have well established antineoplastic effects among patients with a variety of malignancies. Yet relatively little is known about the rash they cause. Our group has completed two clinical trials (n=177) in an effort to try to prevent and palliate this rash, and preliminary observations from our group and from others prompt a series of unanswered questions. Is the EGFR inhibitor-induced rash typically associated with other distressing symptoms such as cutaneous burning and itching? Is it associated with psychological distress, and, if so, to what extent? Can the promising preclinical data with topical menadione lead to the prevention and palliation of this rash in cancer patients? What is the pathophysiology underlying this rash, and might nitric oxide-mediated inflammation be a key component? In view of these unanswered questions, this proposal has the following aims: AIM #1: To utilize focus groups among cancer patients who had previously suffered from an EGFR inhibitor induced rash in an effort to characterize, for the first time, the entire cluster of signs and symptoms associated with this rash. AIM #2: To explore by means of a randomized, placebo-controlled trial, whether topical menadione prevents and palliates this rash and the other aspects of this rash-related symptom cluster. AIM#3: To explore, by means of serial skin biopsies, whether topically applied menadione, which in other settings has been shown to inhibit endothelial nitric oxide synthase, reverses cutaneous alterations of the nitricoxide signaling pathway, thereby leading to decreased keratinocyte apoptosis. PUBLIC HEALTH RELEVANCE: Epidermal growth factor receptor (EGFR) inhibitors are being used with increasing frequency in cancer therapy. These agents cause a rash which occurs on the face, trunk, and arms and is associated with a poorly characterized cluster of symptoms that appears to include itching, pain, and psychological distress. The purpose of this proposal is to better characterize this skin-related symptom cluster from a clinical and basic science standpoint and to test the agent menadione to prevent it all together.